A new synthetic route to benzophenone derivatives

Introduction

2-Aminobenzophenones are usually obtained from N-methylaniline derivatives [1], [2], [3]. Fadda and coworkers [4], [5], [6], [7], [8], [9], [10], [11], [12], [13] studied the recyclization/isomerization of pyridinium salts to anilines in the presence of aqueous alkali, alkylamine or alkylammonium sulphite and observed that the nature and position of substituents in the pyridine ring have a considerable effect on this reaction [7], [8]. The present work was undertaken to study the effect of substituents of picolinium salts 3 on the course of the recyclization reaction.

Results and discussion

2-Pyridylacetophenones 2 were obtained according to the reported method [14]. Compounds 2 were methylated (Scheme 1) to compounds 3 (Schemes 2 and 3 ), which served as direct precursors to the desired products 4 and 5 with an expected broad spectrum of biological effects [15], [16]. Thus, treatment of compound 3a with methylamine furnished products 4a and 5 in low yields (Scheme 2). It can be suggested that the initially formed anhydrobase A undergoes addition of a hydroxide anion to generate the anionic σ-complex B. After ring opening, the recyclization into a benzene ring takes place. As simple α-picolinium salts do not undergo enamine rearrangement in aqueous ethanolic alkali or aqueous alkylamine [17], the formation of 4a and 5 in the present study indicates that the benzoyl group activates the α-methylene group to undergo the rearrangement. However, in the presence of alkylammonium sulphite as a recyclization reagent, the 2-picolinium iodide 3a undergoes rearrangement to give 2-methylaminobenzophenone (4a) in a much-improved yield of 78% (Scheme 3). The mechanism of 3 is consistent with many reported similar cases [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [18]. The sulphite ion being a weak nucleophile undergoes addition to the softest position C-4 in the pyridine ring to generate a 1,4-dihydropyridine of the type A, which then undergoes ring opening under hydrolytic conditions followed by recyclization with elimination of the reagent, forming the product 4a.

Scheme 1

Scheme 2

Scheme 3

The reaction of N-methylpicolinium iodides 3b and 3c with methylammonium sulphite furnished the expected rearrangement products 4b and 4c in 71% and 68% yields, respectively (Scheme 3).

However, the attempted reaction of compound 3d failed to give 2-methylaminobenzophenone, and instead, the parent 4,6-dimethyl-2-pyridylacetophenone (2d) was obtained, apparently, by direct attack of the nucleophile to the CH₃-N bond (S_N2 mechanism) (Scheme 3). Alkyl groups R reduce the electron deficiency of the ring and give rise to steric difficulties for the sulphite ion addition. Accordingly, the yield of R-susbstituted recyclization products decrease, particularly with a 4,6-dimethylpyridine derivative.

3-Substituted pyridines are less susceptible to this effect. This suggests a predominant addition of the sulfite ion to the C-4 atom, so that the initial products are the 1,4-dihydropyridines A, which recyclize into aromatic compounds by elimination of the reagent.

The recyclization of unquaternized 2-pyridylacetophenone 2a was also studied [9]. Upon treatment of 2a with aqueous methylammonium sulphite, the amine fragment was exchanged for a methylamine fragment in the open chain intermediate and the product of the recyclization reaction was 4a obtained in a 35% yield (Scheme 4). However, the bulk of the compound 2a was recovered unchanged. There is no evidence for the formation of 2-aminobenzophenone as a product of the recyclization reaction by spectroscopic data. All attempts to obtain the latter compound by treatment of compound 2a with aqueous ammonium sulphite failed.

Scheme 4

When zinc chloride was used as a catalyst [8] in the reaction of 2a, the yield of product 4a increased to 51% (Scheme 4). It can be noted that the yield of 4a was invariably less in the presence of aqueous alkylamine than in the presence of methylammonium sulphite as a recyclizing agent. It was also demonstrated that the treatment of N-ethyl-2-picolinium iodide (6, analog of 2a, not shown) with methylammonium sulphite led to the formation of a mixture of 2-methylaminobenzophenone (4a) (60%), 2-hydroxybenzophenone (5) (12%) and 2-pyridylacetophenone (2a) (10%).

Experimental

Melting points are uncorrected. The infrared (IR) spectra were recorded in KBr disks on a Mattson 5000 FTIR spectrometer. The ¹H-NMR spectra were determined on a Bruker WPSY 200 MHz spectrometer in DMSO-d₆ with tetramethylsilane (TMS) as an internal standard. The electron ionization (EI) mass spectra were recorded at 70 eV with Varian MAT 311. Elemental analyses (C, H and N) were carried out at the Faculty of Science, Cairo University, Egypt. Compounds 2a [14], 2b [14], [19], 2c [18], [20], 2d [21], [22], 4a [23], 4c [24], 5 [25] and 6 [19] were synthesized as previously reported.